# Dissecting the role of CD8+ T cells in atherosclerosis

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $654,084

## Abstract

PROJECT SUMMARY
Atherosclerotic cardiovascular disease (ACVD) is the leading cause of mortality and disability worldwide, even
in optimally treated patients. While the impact of many immune cell types on atherosclerosis is well-
established, the contribution of CD8+ T cells to the disease pathology remains to be further elucidated. In
previous work using unbiased single-cell (sc) analyses to study the immune composition of human
atherosclerotic plaques we found new dysregulations tissue resident memory (TRM) CD8+ T cells associated
with clinical CV outcomes. CD8+ T cell infiltrates have been described in both early and advanced human
atherosclerotic plaques and their cytotoxic effector functions contribute to plaque progression in mice.
However, information on how CD8+ T cells contribute to atherosclerotic plaque vulnerability and cardiovascular
(CV) events is limited and remains to be fully understood. In preliminary sc studies, we identified the
transcriptional regulator Zeb 2 as a top candidate master regulator of plaque CD8+ T cell proatherogenic
alterations. We hypothesize that Zeb2 is a key driver of the activation and cytotoxicity of effector TRM CD8+ T
cells in atherosclerotic plaques and that these alterations contribute to disease progression and plaque
vulnerability. We also contend that its downregulation is implicated in the reprogramming of PD-1+ TRM CD8+ T
cells found in plaques of patients with recent stroke. We propose two independent aims to study the role of
Zeb2 in plaque vulnerability and CV events. In Aim 1, we will dissect the Zeb2-mediated activation of plaque
TRM CD8+ T cells and determine their association with plaque vulnerability at pathology. In this Aim we will also
determine the effect of Zeb2 deficiency selectively in activated TRM CD8+ on atherosclerosis in mice. In Aim 2,
we will identify how Zeb2 mediates TRM CD8+ T cell dysregulations of adverse CV outcomes and determine
how Zeb2 downregulation in all CD8+ T cell affect their exhaustion reprogramming and whether these
alterations contribute to plaque size and vulnerability in vivo. These studies will address important gaps in
knowledge in CD8+ T cell biology in atherosclerosis, and will tackle previously unappreciated cellular and
molecular mechanisms associated with plaque rupture/erosion that may contribute to clinical CV outcomes.
We foresee that this information may help guide the future design of precise, molecularly targeted
immunotherapies to prevent CV outcomes in patients with carotid and coronary disease.

## Key facts

- **NIH application ID:** 10034860
- **Project number:** 1R01HL153712-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Chiara Giannarelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $654,084
- **Award type:** 1
- **Project period:** 2020-08-20 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10034860

## Citation

> US National Institutes of Health, RePORTER application 10034860, Dissecting the role of CD8+ T cells in atherosclerosis (1R01HL153712-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10034860. Licensed CC0.

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